Pharmaceutical compositions of 5,6-dialkoxy-2-aminobenzimidazoles and method for treating hypertension

ABSTRACT

AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS WHEREIN R and R1 are each lower alkyl are disclosed as useful for the treatment of hypertension in mammals, including humans. Novel compounds of formula:

United States Patent [191 Skaletzky [75] Inventor: Louis L. Skaletzky,Kalamazoo,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: May 28, 1974 [21] Appl. No.: 473,683

Related US. Application Data [63] Continuation of Ser. No. 361,277, May17, 1973,

abandoned.

[52] US. Cl. 424/273 [51] Int. Cl. A61K 31/415 [58] Field of Search424/273 [56] References Cited UNITED STATES PATENTS 3,705,175 12/1972Magdanyi et al. 424/273 Dec. 23, 1975 Primary Examiner-Albert T. MeyersAssistant Examiner-Daren M. Stephens Attorney, Agent, or FirmJohn J.Killinger; Roman Saliwanchik and their pharmaceutically acceptable acidaddition salts wherein R and R are each lower alkyl are disclosed asuseful for the treatment of hypertension in mammals, including humans.

5 Claims, No Drawings PHARMACEUTICAL COMPOSITIONS OFS,6-DIALKOXY-2-AMINOBENZIMIDAZOLES AND METHOD FOR TREATING HYPERTENSIONCROSS REFERENCE TO RELATED APPLICATIONS This application is acontinuation of application Ser. No. 361,277, filed May 17, 1973, nowabandoned.

BACKGROUND OF THE INVENTION 1. Field of the Invention The inventionconcerns novel 5,6-dialkoxy-2- aminobenzimidazoles and their use inpreparing therapeutic compositions for the treatment of hypertension inmammals.

2. Description of the Prior Art Belgian Pat. No. 768,300 of June 9, 1971discloses 2-acetamido-5,6-dialkoxybenzimidazoles and their use ashypotensive agents.

In general, a large number of 2-acylamidobenzimidazoles are known to beuseful hypotensive agents. However, the corresponding2-aminobenzimidazoles have not been previously known to possess thisuseful property. In fact, a number of 2-aminobenzimidazolescorresponding toknown hypotensive 2-acylamidobenzimidazoles do notsignificantly lower blood pressures in mammals. For example, although2-acetamido-5,6- dimethylbenzimidazole possesses hypotensive properties(Belgian Pat. No. 768,300), the corresponding.

2-amino-5,6-dimethylbenzimidazole does not. Similarly, Belgian Pat. No.768,300 discloses that 2- acetamido-4,7-dialkoxybenzimidazoles possesshypotensive properties. However, the corresponding 2- amino-compound,for example, 2-amino-4,7-dimethoxybenzimidazole, does not significantlyreduce blood pressures in mammals.

Subsequent to our invention, 2-amino-5,6-dimethoxybenzimidazole wasdisclosed as an intermediate for hypotensive 2-acylamidobenzimidazolesin Bellasio et 21]., Farm. Ed. Sci., 28(2), 164-82 (1973).

In view of the above, my finding that the 2-amino-5,6-dialkoxybenzimidazoles are useful for the treatment of hypertensionin mammals is unexpected and surprising.

SUMMARY OF THE INVENTION The invention comprises compounds selected fromthose of formula:

and the pharmaceutically acceptable acid addition salts thereof whereinR and R are each lower alkyl.

The term lower alkyl is used herein to mean alkyl having from 1 to 4carbon atoms, inclusive. Illustrative of lower alkyl are methyl, ethyl,propyl, butyl, and isomeric forms thereof.

The invention also comprises therapeutic compositions containing thecompounds (I) or the pharmaceutically acceptable acid addition saltsthereof as the 2 essential active ingredient and methods of treatinghypertension in mammals, including humans, with ef fective amounts ofthe compounds (I). The compounds and compositions of the invention 5 areuseful for treating hypertension in mammals, in-

eluding humans.

DETAILED DESCRIPTION OF THE INVENTION The compounds (I) of the inventionare conveniently prepared by the method of Joseph, J. Med. Chem, 6, 601,(1963). In general, the method comprises condensing 'an appropriateo-phenylenediamine of formula:

wherein R and R are as defined above; with cyanogen bromide to obtainthe hydrobromide saltof the corresponding compound I). The hydrobromidesalt may be separated by conventional means when desired or the reactionmixture may be basified with ammonium hydroxide or other strong bases toobtain the compound (I) free base.

The compounds. (I) of the invention can exist in either the free baseform or in the form of an acid addition salt. The acid addition saltsare prepared by reacting the free base (I) with a stoichiometricproportion of an appropriate acid such as hydrochloric acid. The methodis well known to those skilled in the art and may be carried out inaqueous or non-aqueous media such as ethanol, ether, ethyl acetate andthe'like.

The pharmaceutically acceptable acid addition salts may be used for thesame purposes as the free base. Illustrative of pharmaceuticallyacceptable acid addition salts are those formed upon reaction of thecompounds (I) with hydrochloric acid, hydrobromic acid,

PREPARATION l l ,2-Diamino-4,S-dimethoxybenzene A Parr low pressurehydrogenation apparatus is charged with 10 grams (0.044 mole) ofl,2-dinitro-4,5-

dimethoxyben zene, 1.0 grams of platinum oxide and ml. of absoluteethanol. While continually agitating the reaction mixture, hydrogenationis carried out for one hour under a hydrogen pressure of from 2 to 3atmospheres. At the end of this period, excess hydrogen is vented andthe reaction mixture is filtered to remove solid residues. The filtrateis a solvent mixture containing crude l,2-diamino-4,5-dimethoxybenzene.

The following examples 'describe the manner and process of making andusing the invention and set forth the best mode contemplated by theinventor of carrying out the invention but are not to be construed aslimit- EXAMPLE 1 An appropriate reaction vessel is charged with thecrude reaction mixture containing 1,2-diamino-4,5- dimethoxybenzeneobtained in Preparation 1, supra. A solution of 4.7 gms. (0.044 mole) ofcyanogen bromide in 50 ml. of ethanol is added and the resulting mixturestirred overnight at room temperature, under a nitrogen gas atmosphere.At the end of this period solvent is removed under reduced atmosphericpressure and the residue extracted with isopropanol. The residue is thenrecrystallized from a mixture of methanol-ether to give 3.15 gms. (26%of theory based on starting 1,2-dinitro- 4,5-dimethoxybenzene) of2-amino-5,6-dimethoxybenzimidazole hydrobromide in the form of a pinksolid, M.P. 280C. to 281C. (dec.). Structure of the product is confirmedby elemental analysis.

Similarly, following the above procedure but replacing the reactionmixture containing 4,5-diamino- 1,2-dimethoxybenzene as used thereinwith 1,2- diamino-4,S-dibutoxybenzene there is obtained 2-amino-S,6-dibutoxybenzimidazole hydrobromide.

EXAMPLE 2 Repeating the procedure of Example 1., supra. but treating thesolution obtained upon dissolving the extracted residue in themethanol-ether mixture with sufficient ammonium hydroxide to give a pHof circa 4-6, there is obtained upon recrystallization 2-amino-5,6-dimethoxybenzimidazole free base.

This invention relates also to pharmaceutical dosage unit forms forsystemic administration (oral and parenteral administration) which areuseful in treating hypertension in mammals, including humans. The termdosage unit form as used in this specification and in the claims refersto physically discrete units suitable as unitary dosages for mammaliansubjects, each unit containing a predetermined quantity of the essentialactive ingredient, i.e.; a compound (I) or a pharmaceutically acceptableacid addition salt thereof, calculated to produce the desired effect incombination with the required pharmaceutical means which adapt saidingredient for systemic administration. Examples of dosage unit forms inaccordance with this invention are tablets, capsules, orallyadministered liquid preparations in liquid vehicles, sterilepreparations in liquid vehicles, sterile preparations in liquid vehiclesfor intramuscular and intravenous administration, suppositories, andsterile dry preparations for the extemporaneous preparation of sterileinjectable preparations in a liquid vehicle. Solid diluents or carriersfor the solid oral pharmaceutical dosage unit forms are, for example,selected from the group consisting of lipids, carbohydrates, proteinsand mineral solids, for example, starch, sucrose, kaolin, dicalciumphosphate, gelatin, acacia, corn syrup, corn starch, talc and the like.Capsules both hard and soft are formulated with suitable diluents andexcipients, for example, edible oils, talc, calcium carbonate and thelike and also calcium stearate. Liquid preparations for oraladministration are prepared in water or aqueous vehicles whichadvantageously contain suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, acacia, polyvinyl pyr- 4rolidone, polyvinyl alcohol and the like. In the case of injectableforms, they must be sterile and must be fluid to the extent that easysyringeability exists. 'Such preparations must be stable under theconditions of manufacble oils, ethanol and polyols, for example,glycerol,

propylene glycol, liquid polyethylene glycol, and the like. Any solidpreparations for subsequent extemporaneous preparation of sterileinjectable preparations are sterilized, preferably by exposure to asterilizing gas, for example, ethylene oxide. The aforesaid carriers,vehicles, diluents, excipients, preservatives, isotonic agents and thelike constitute the pharmaceutical means which adapt the preparationsfor systemic administration.

The effective amount of a compound (I) 'or the pharmaceuticallyacceptable acid addition salts thereof required for administration to amammal suffering from hypertension is within the range of from about 1mg. per kilogram of body weight to about 50 mg. per kilogram of bodyweight of the recipient, daily. Preferably, the amount is within therange of from about 2.0 mg. per kilogram of body weight to about 25.0mg. per kilogram of body weight on a daily basis.

The pharmaceutical dosage unit forms are prepared in accordance with thepreceding general description to provide from about 25 to about 250 mg.of the essential active ingredient per dosage unit form.

Advantageously the compounds of the invention (I) and pharmaceuticallyacceptable acid addition salts thereof may also be combined withsedatives and tranquilizers such as phenobarbital, pentobarbital,chloral hydrate, chlorpromazine, thioridazine, diazepam and the likewhen sedation or tranquilization of the mam-- mal being treated is alsodesired.

Combinations with other antihypertensive agents such as hydralazinehydrochloride, hexamethonium bromide, mecamylamine hydrochloride,phenoxybenzamine hydrochloride, guanethidine sulfate, methyldopa and thelike may be advantageous in over-coming developing tolerance orresistance to such agents.

Combinations with antidepressant agents such as d-amphetamine,pheniprazine hydrochloride, tranylcypromine, imipramine, desipramine,amitriptyline, nortriptyline, protriptyline and methylphenidatehydrochloride may be made when considered desirable.

Combinations with diuretic agents such as ethoxzolamide,hydrochlorothiazide, trichlormethiazide, acetazolamide, chlorthalidone,triamterene, quinethazone, cyclothiazide, chlorothiazide, benzthiazideand the like may also be advantageous in the treatment of hypertension.

Illustratively, in combination with the compounds of the invention, theother active compounds are administered with dosages as indicated:anti-anxiety and tranquilizing agents: chlorpromazine (5-50 mg.),thioridazine (5-100 mg), haloperidol (0.5-5 mg), meprobamate (-400 mg),ectylurea (100-300 mg.), chlordiazepoxide (5-50 mg.) and diazepam (2-15mg); antidepressants such as amitriptyline hydrochloride (10-50 mg.),methylphenidate hydrochloride (5-20 mg.), d-amphetamine sulfate (2-15mg.) and metham- EXAMPLE 3 One thousand tablets for oral use, eachcontaining 250 mg. of essential active ingredient are prepared from thefollowing ingredients:

essential active ingredient 250 Gm. dicalcium phosphate 150 Gm.methylcellulose, U.S.P.( l5 cps) 6.5 Gm. talc 20 Gm. calcium stearate2.5 Gm.

The essential active ingredient and dicalcium phosphate are mixed well,granulated with 7.5% aqueous solution of methylcellulose, passed througha No. 8 screen and dried carefully. The dried granules are passedthrough a No. 12 screen, mixed with the talc and stearate and compressedinto tablets. These tablets are useful in the treatment of hypertensionin adult humans at a dose of 1 tablet two or three times a day.

EXAMPLE 4 One thousand two-piece hard gelatin capsules for oral use,each capsule containing 25 mg. of essential active ingredient areprepared from the following ingredients:

essential active ingredient 25 Gm. lactose, U.S.P. 100 Gm. starch,U.S.P. Gm. talc, U.S.P. 5 Gm. calcium stearate l Gm.

The finely powdered materials are mixed thoroughly, then filled intohard gelatin capsules of appropriate size.

A satisfactory clinical response is obtained in adults showinghypertension with 1 capsule six times a day.

EXAMPLE 5 One-piece soft elastic capsules for oral use, each containing50 mg. of essential active ingredient, are prepared in the usual mannerby first dispersing the powdered active material in sufficient corn oilto render the material capsulatable.

One capsule four times a day is useful in the treatment of moderatehypertension in adult humans.

EXAMPLE 6 An aqueous oral preparation containing in each teaspoonful(5ml.) 50 mg. of essential active ingredient hydrochloride is preparedfrom the following:

essential active ingredient Gm.

(hydrochloride) methylparaben, U.S.P. 7.5 Gm. propylparaben, U.S.P. 2.5Gm. saccharin sodium 12.5 Gm. glycerin 3,000 ml. tragacanth powder 10Gm. orange oil flavor l0 Gm. RD. and C. orange dye 7.5 Gm. deionizedwater. q.s. to 10,000 ml.

The foregoing aqueous preparation is useful in the treatment of adultsfor hypertension at a dose of one teaspoonful four times a day.

EXAMPLE 7 One thousand tablets for oral administration, each containing25 mg. of essential active ingredient and 16.2 mg. of phenobarbital areprepared from the following ingredients:

essential active ingredient, 25 Gm.

micronized phenobarbital 16.2 Grn.

lactosc Gm.

starch l5 Gm.

magnesium stearate 1.5 Gm.

The ingredients are thoroughly mixed and slugged. The slugs are brokendown by forcing through a screen and the resulting granules are thencompressed into tablets.

These tablets are useful in treating excited, hypertensive mammals suchas dogs at a dose of l to 3 tablets, depending on the weight of theanimal and its conditlon.

EXAMPLE 8 A sterile aqueous suspension suitable for intramuscularinjection and containing in each milliliter 100 mg. of essential activeingredient is prepared from the following ingredients:

essential active ingredient 10 Gm. polyethylene glycol 4000, U.S.P. 3Gm. sodium chloride 0.9 Gm. polysorbate 80, U.S.P. 0.4 Gm. sodiummetabisulfite 0.1 Gm. methylparaben, U.S.P. 0.18 Gm. propylparaben,U.S.P. 0.02 Gm. water for injection, q.s. to 100 ml.

The above sterile injectable is useful in the treatment of hypertensionat a dose of l or 2 ml. administered daily.

EXAMPLE 9 One thousand suppositories, each weighing 2.5 Gm. andcontaining 250 mg. of essential active ingredient, are prepared from thefollowing ingredients:

essential active ingredient 250 Gm. propylene glycol I65 Grn.polyethylene glycol (PEG) 2,500 Gm.

The essential active ingredient is added to the propylene glycol and themixture milled until uniformly dispersed. The PEG 4000 is melted and thepropylene glycol dispersion added. The suspension is poured into moldsand allowed to cool and solidify.

7 These suppositories are useful in the treatment of hypertension inmammals at a dose of l suppository administered rectally twice a day.

EXAMPLE One thousand hard gelatin capsules for oral use, each containing50 mg. of essential active ingredient and mg. of hydrochlorothiazide,are prepared from the following ingredients:

essential active ingredient, 50 Gm.

micronized hydrochloruthiazide 25 Grn.

starch I25 Gm.

talc 25 Gm.

magnesium stearate l.5 Gm.

One capsule four times a day is useful in the relief of moderatehypertension in adult humans.

EXAMPLE I 1 Ten thousand scored tablets for oral use, each containing 50mg. of essential active ingredient and 0.08 mg. of reserpine, areprepared from the following ingredients, using the procedure of Example7, supra:

essential active ingredient 500 Gm.

micronized reserpine 0.8 Gm.

lactose L500 Gm.

corn starch 500 Gm.

talc 500 Gm.

calcium stcaratc 25 Gm.

This combination of active materials is effective in reducinghypertension in adult humans. The dose is one-half to two tablets threeto four times a day, depending on the severity of the condition.

EXAMPLE l2 Aqueous Suspension An aqueous suspension for oraladministration is prepared by suspending the essential active ingredientat a concentration of 5 mg./ml. in an aqueous solution containing 1% ofsodium carboxymethylcellulose. This suspension is used for bringingabout hypotensive effects in unanesthetized normotensive rats. The ratsare prepared for measuring blood pressure directly from the aortathrough a chronic indwelling cannula [method of Weeks and Jones, Proc.Soc. Exptl. Biol. and Med., 104, 646, (1960)].

Employing groups of four rats each (average weight 285 to 365 grams),varying amounts of essential active ingredient are orally administeredto the rats, and arterial blood pressure measurements obtained prior to,and at 4 hours and 24 hours after administration. The blood pressuremeasurements obtained and the reduction of blood pressure obtained ateach dosage level are set forth in Table I below.

TABLE 1 TABLE l-continued Oral Rat Weight (gm) Initial B.P.Change DoseRat B.P. mm Hg mg/kg No. Initial 24 hr mm Hg. 4 hr 24 hr 43 325 330 I40l0 I4 47 315 3I5 I30 -30 30 avg. 365 364 I36 22 23 I25 I62 320 315 I28 88 I64 300 300 I36 16 I8 295 290 I34 8 I0 I74 305 305 I32 I4 2 avg. 305303 I33 l2 l0 6.25 I87 290 285 I38 I 8 6 I89 290 285 I36 I0 6 6.25 224300 300 I28 20 I 8 229 290 290 I44 l2 l4 avg. 293 290 I37 I 5 I I 3.l2I96 300 300 I40 I6 10 2I5 294 290 I30 I4 6 219 300 295 I34 I8 4 227 290285 I40 -I6 I2 avg. 296 293 136 I6 8 The above Table I. points out theeffectiveness of the essential active ingredient in reducing bloodpressure in a mammal. A compound is deemed effective, which will reducemean arterial pressures by at least 10 mm. of mercury. No toxic effectswere noted in the test animals.

EXAMPLE 13 Following the procedure of the preceding Examples 3 to 12,inclusive, similar dosage forms are prepared by substituting anequivalent amount of the other inventive compounds or their acidaddition salts, such as, for example,

2-amino-5,6-dimethoxybenzimidazole,

2-amino-5,6-diethoxybenzimidazole,

2-amino-5,6-diisopropoxybenzimidazole, 2-amino-5,6-dibutoxybenzimidazoleand like compounds of the formula (I).

I claim:

1. A pharmaceutical dosage unit form adapted to systemic administrationto obtain antihypertensive effects consisting essentially of aneffective amount for said effects of a compound of the formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein Rand R are each lower alkyl; in combination with pharmaceutical meansselected from the group consisting of carriers, vehicles, diluents,excipients, preservatives, and isotonic agents which adapt the compoundfor systemic administration.

2. The composition of claim 1 wherein said compound is2-amino-5,6-dimethoxybenzimidazole hydrobromide.

3. A method of obtaining antihypertensive effects in a mammal whichconsists essentially of administering systemically to said mammal apharmaceutical dosage unit form supplying an effective amount forantihypertensive effect of a compound of formula:

NH Y or a pharmaceutically acceptable acid addition salt thereof whereinR and R are each lower alkyl.

2-amino-5,6-dimethoxybenzimidazole hydrobromide.

1. A PHARMACEUTICAL DOSAGE UNIT FORM ADAPTED TO SYSTEMIC ADMINISTRATIONTO OBTAIN ANTIHYPERTENSIVE EFFECTS CONSISTING ESSENTIALLY OF ANEFFECTIVE AMOUNT FOR SAID EFFECTS OF A COMPOUND OF THE FORMULA:
 2. Thecomposition of claim 1 wherein said compound is2-amino-5,6-dimethoxybenzimidazole hydrobromide.
 3. A METHOD OFOBTAINING ANTIHYPERTENSIVE EFFECTS IN A MANMAL WHICH CONSISTSESSENTIALLY OF ADMINISTERIN SYSTEMICALLY TO SAID MAMMAL A PHARMACEUTICALDOSAGE UNIT FORM SUPPLYING AN EFFECTIVE AMOUNT OF ANTIHYPERTENSIVEEFFECT OF A COMPOUND OF FORMULA:
 4. The method of claim 3 wherein theamount of compound administered is within the range of from about 1 mg.per kg. to about 50 mg. per kg. of weight of said mammal, on a dailybasis.
 5. The method of claim 3 wherein said compound is2-amino-5,6-dimethoxybenzimidazole hydrobromide.